2002 Albert Lasker Award

James E. Darnell, Jr., M.D.

LABORATORY OF MOLECULAR CELL BIOLOGY

Responsible for the various tasks required in turning genetic information into working proteins, ribonucleic acids are one of the most essential players in the life of a cell. First discovered in 1868, RNA today remains the subject of intense scientific scrutiny. Over the course of a career dedicated to understanding the intricate workings of gene transcription, Rockefeller University scientist James E. Darnell Jr. has revealed some of RNA’s most secretive and surprising mechanisms. For his half-century of illuminating research, Dr. Darnell received the 2002 Albert Lasker Award for Special Achievement in Medical Science.

In 1963, Dr. Darnell described a phenomenon he termed “RNA processing,” a step in the process of gene transcription, which had only recently been elucidated in bacterial systems. Working with mammalian cells — which differ from bacterial cells in that they contain a nucleus, where RNA is created — Dr. Darnell observed that very long strings of RNA disappear from the cell nucleus and that subsequently, shorter RNAs resembling the absent longer ones appear in the cytoplasm. Mammalian cells, he concluded, must distill their massive, immature nuclear RNA into shorter, mature forms that are individually coded for specific purposes by specific segments of the genome.

Dr. Darnell carried the principles of his finding — which he made in ribosomal RNA, part of the construction crew that builds cellular proteins — to other long nuclear RNA, including the longest one, which he named heterogeneous nuclear RNA (hnRNA). His hypothesis, that hnRNA is the precursor of the better known messenger RNA — which carries the genetic blueprint for protein building — soon bore fruit when he found a structural correlation between the two. Certain hnRNAs and nearly all messenger RNAs have a “tail” of adenine nucleotides at one end. Dr. Darnell followed this discovery with the observation that when an hnRNA string with an adenine tail disappears from the nucleus, a messenger RNA with the same tail then appears in the cytoplasm, suggesting a causal link between the two. When he found a second similarity — a cap at the end of the string opposite the adenine tail — he faced a conundrum. Scientific dogma had it that the order of nucleotides in any RNA mirrors that of DNA, whether the RNA is modeled from somewhere in the middle of the DNA or from one of the ends. The matching of a nuclear RNA to its cytoplasmic product by two end pieces glued together was surprising, but the concept was soon proven by colleagues at other institutions and called RNA splicing.

With the knowledge of RNA processing and splicing, Dr. Darnell next examined how cells begin the process of transcription and how they activate particular segments of DNA. Having moved to Rockefeller University in 1974, he found in the early 1980s that cells retain their specificity only in the context of their natural environment. Away from other liver cells, for example, a single liver cell stops producing liver-specific RNA, though it continues to make RNA for more generic cellular tasks. To pinpoint the signals responsible, which he believed must be coming from outside the cell, Dr. Darnell took a closer look at interferons (IFN), proteins that warn a cell when it’s time to raise its genetic defenses against harmful microbes. Introducing IFNβ into cell cultures, he watched as a particular type of mRNA accumulated in the cytoplasm, unaccompanied by any new protein synthesis. Analyzing the mRNA led him to the segment of DNA that had been activated, and the lack of new proteins told him that the cell contained its own, usually dormant, IFN-responsive transcription factor. By isolating a particular stretch of DNA from IFN-treated cells, he was able to call out of hiding the proteins that make up that factor, which, partly because they respond to signals very quickly, he called “STATs.” Dr. Darnell then traced the chemical relay that activates the STATs after IFN contact, called the Jak-Stat pathway.

Dr. Darnell’s work provided the first complete explanation of how a cell translates its genes, and how it can do so quickly to change course in response to environmental signals. Researchers have since discovered several other Stat proteins, which activate genes for a wide variety of purposes, as well as similar proteins in other organisms. Certain Stat pathways may also hold direct therapeutic value, in diseases as varied as anemia and cancer.

CAREER

Dr. Darnell received his M.D. in 1955 from the Washington University School of Medicine. His career has included poliovirus research with Harry Eagle at the National Institute of Allergy and Infectious Diseases, research with François Jacob at the Institut Pasteur in Paris and academic appointments at the Massachusetts Institute of Technology, the Albert Einstein College of Medicine and Columbia University. In 1974 Dr. Darnell joined Rockefeller as Vincent Astor Professor, and from 1990 to 1991 he was vice president for academic affairs. In addition to the Lasker Award, Dr. Darnell has received the 2003 National Medal of Science, the 1997 Passano Award, the 1994 Paul Janssen Prize in Advanced Biotechnology and Medicine and the 1986 Gairdner Foundation International Award. He is the coauthor with S.E. Luria of General Virology and the founding author with Harvey Lodish and David Baltimore of Molecular Cell Biology, now in its fifth edition. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences and a foreign member of The Royal Society and the Royal Swedish Academy of Sciences.

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